Potential New Therapeutic Approach Identified for Two Types of Pancreatic Cancer

5/19/2014

NEW ORLEANS — Blocking the protein CD47, which was found at elevated levels on both pancreatic neuroendocrine tumor cells and pancreatic ductal adenocarcinoma cells, caused tumor regression in preclinical models of both these types of pancreatic cancer, according to results presented here at the AACR special conference on Pancreatic Cancer: Innovations in Research and Treatment, held May 18–21.

“We are optimistic that targeting CD47 in this way could provide a new approach for treating patients with pancreatic cancer who have a desperate need for improved treatment options,” added Krampitz, who is also a general surgery resident in the Department of Surgery at Stanford Hospital and Clinics.

Krampitz and Jeffrey A. Norton, M.D., chief of the Divisions of General Surgery and Surgical Oncology at Stanford University School of Medicine, obtained tumor samples from 39 patients with pancreatic neuroendocrine tumors who were undergoing surgery to remove their cancers. Analysis of 19 of these samples showed that some cells in the tumors had characteristics of tumor-initiating cells and that these cells, as well as the bulk tumor cells, had elevated levels of CD47.

The researchers also obtained tumor samples from 39 patients with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, who were undergoing surgical resection. As with the pancreatic neuroendocrine tumors, all the pancreatic ductal adenocarcinoma cells in the samples examined had elevated levels of CD47.

They then tested the effects of blocking CD47 function in a number of different preclinical models of pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinoma. Antitumor activity was observed in each model. In one model, in which mice were transplanted with tumors from either patients with pancreatic neuroendocrine tumors or those with pancreatic ductal adenocarcinoma, treatment with a monoclonal antibody that recognizes and attaches to CD47 and blocks its function caused dramatic tumor regression.

“CD47 is a ‘don’t-eat-me’ signal,” explained Krampitz. “Most cells have this protein on their surface and it stops them from being removed by immune cells called macrophages. As cells age or become damaged, they lose expression of CD47, which leads to their elimination by macrophages through a process called programmed cell removal. Pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinomas have co-opted CD47 to help them avoid removal by the immune system. We have preliminary evidence that suggests that by blocking the don’t-eat-me signal, our monoclonal antibody promotes the clearance of cancer cells by programmed cell removal.

This study was supported by funds from the Virginia and D.K. Ludwig Foundation for Cancer Research, the National Cancer Institute, the A. P. Giannini Foundation, the Siebel Stem Cell Institute and the Thomas and Stacey Siebel Foundation, an Anonymous Donors Fund, and the American College of Surgeons. Krampitz declares no conflicts of interest.